Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)2Zn(CF2H)2] and Improved Synthesis of the ICHF2 Precursor

Article
Continuous flow
Drug substance
Process development

Complex [(DMPU)2Zn(CF2H)2] 1 is a crystalline organometallic reagent with utility in various catalytic difluoromethylation reactions under mild conditions. Unfortunately, this reagent isn’t commercially available, and the procedure for the preparation of this air- and moisture-sensitive zinc complex has only been reported on a small scale.

In collaboration with Pfizer, our teams developed a continuous process for the preparation of reagent 1 on >100 g scale by using a continuous stirred-tank reactor. In this article, we explain the key to success was the design of a continuous reactive crystallization process in which the precipitation of the zinc complex 1 is driven by its low solubility in the reaction solvent. The improved synthesis of the iododifluoromethane precursor 2 from readily available bromodifluoroacetic acid further enabled the synthesis of complex 1 on a larger scale.

Read the entire article to learn more about how we utilized a continuous process to prepare reagent 1 on >100 g scale.

View the full article (via ACS Publications)